Natural-looking skin is influenced by a number of physiological and genetic factors. Standard definitions of beautiful skin include skin having a transparent quality with uniform undertones of color and no visible or tactile discontinuities. The basis for this natural-looking appearance is in the skin structure itself. The outer layer of human skin is a semi-transparent layer known as the stratum corneum. The transparency of the stratum corneum permits glimpses of the deeper layers of skin, where blood vessels and pigments reside. The pale reddish hue of the blood vessels' hemoglobin, and the brown/black hue of melanin that is the primary skin pigment, combine to produce the skin's color. Ideal skin should also be smooth and even, with no apparent surface flaws in addition to having the transparent look with uniform color distribution.
Skin is composed of a top layer, the epidermis, which is approximately 20 cell layers or about 0.1 mm in thickness, and a lower layer, the dermis, which is from about 1 to about 4 mm in thickness and contains small blood vessels, collagen, elastin and fibroblasts. The dermis provides structural support and nutrients to the epidermis. Aging has been shown to increase cellular heterogeneity of the epidermal layer. Aging does not affect the number of cell layers in the epidermis, but the overall thickness decreases. The supporting dermis is known to thin with age and exposure to the sun and environmental contaminants. The dermal layer provides the support and blood supply for the epidermis, therefore the dermal layer is important in maintaining the elasticity and appearance of the skin.
Considerable effort has been expended to find ways to prevent adverse changes in the skin brought about by ultraviolet (UV) exposure and other causes. Preventative approaches include physically blocking or absorbing the UV radiation before it can enter the skin using UV absorbing compounds. Skin problems in aging individuals can result from a variety of extrinsic or intrinsic factors such as harmful UV radiation from the sun, exposure to the environment, stress, fatigue, disease, or a combination thereof.
Many people at different stages of their life are concerned with the degree of pigmentation of their skin and may wish to reduce the skin darkening, or may wish to lighten or even-tone their natural skin color. The mechanism by which skin pigmentation is formed, melanogenesis, is particularly complex and schematically involves the following main steps: Tyrosine→L-Dopa→Dopaquinone→Dopachrome→Melanins. The first two reactions in this series are catalyzed by the enzyme tyrosinase. The activity of tyrosinase is promoted by the action of a-melanocyte stimulating hormone or UV rays. It is well established that a substance has a depigmenting effect if it acts directly on the vitality of the epidermal melanocytes where melanogenesis normally occurs and/or if it interferes with one of the stages in melanin biosynthesis. Pigmentation disorders can take a variety of forms like hyperpigmentation, hypopigmentation, and uneven pigmentation, and include but are not limited to melasma (mask of pregnancy or chloasma), liver spots (which often develop with age) and leukoderma such as vitiligo. Some of the pigmentation occurs as a side effect of birth control pills, as a result of skin damage such as a persistent result of acne, burns, bites and other skin injuries, as after-burn scars, as cicatrical spots, as stretch mark scars, and as dark circles and puffiness under and around the eyes. The degree of pigmentation disorders of the skin in many cases increases with the age of the individuals. Because of the involvement of tyrosinase in melanogensis, tyrosinase inhibition assays are often used to screen potential skin lightening agents. Some mushroom tyrosinases (such as that from Agaricus bisporus) are homologous with mammalian tyrosinase, and mushroom tyrosinase is often used in inhibition assays due to its ready commercial availability. However, the enzyme inhibition assays may not be as good an indicator of activity as assays which are more similar to the intended clinical or cosmetic use, such as the MatTek Corporation's MelanoDerm™ Skin Model (a system which consists of normal, human-derived epidermal keratinocytes and melanocytes formed into a multilayered model of human epidermis).
In the United States, the most commonly used treatment for hyperpigmentation is 1,4-benzenediol, which is known as hydroquinone. Treatment with hydroquinone interferes with the action of tyrosinase, which is an enzyme used in the synthesis of melanin, and compositions are sold across the counter at about 2% hydroquinone and by prescription at higher concentrations. Hydroquinone compositions are effective but have some undesirable side effects. These can be burning, redness, sensitization and irritation in some patients. U.S. Pat. No. 4,526,179 refers to certain hydroquinone fatty esters that have good activity and are less irritating and more stable than hydroquinone. Japanese Patent Application No. 27909/86 (JP 61-27909) refers to other hydroquinone derivatives that do not have the drawbacks of hydroquinone but that have relatively poor efficacy. Other compounds with a hydroquinone core structure have been described in the patent literature, for example, U.S. Pat. No. 5,449,518 refers to 2,5-dihydroxyphenyl carboxylic acid derivatives, and European Patent Application EP 341,664A1 and PCT International Publication WO 99/15148 refer to certain resorcinol derivatives as tyrosinase inhibitors.
A variety of additional agents have been applied to the skin to lighten the skin. Such agents include but are not limited to kojic acid, licorice and its derivatives, ascorbic acid and its derivatives, arbutin, bearberry, Glycyrrhiza glabra and its derivatives, Chlorella vulgaris extract, perilla extract, and coconut fruit extract. Perilla extract is disclosed as a whitening agent in U.S. Pat. No. 5,980,904 and Japanese Publications Nos. 07-025742, 07-187989, 10-265322, 2001-163759 and 2001-181173. Coconut fruit extract is disclosed as a whitening agent in Japanese Patent No. 2896815 B2.
Resorcinol (1,3-benzenediol) derivatives have been used to provide cosmetic benefits to skin and hair. 4-Substituted resorcinol derivatives have been used for skin lightening; see, for example, U.S. Pat. Nos. 4,959,393, 6,132,740, 6,504,037, U.S. Patent Application Publication No. 2008/0131382, and Japanese Published Patent Application Nos. JP 2001-01 0925 and JP 2000-327557. Resorcinol derivative dimers which are inhibitors of tyrosinase are disclosed in U.S. Pat. No. 5,399,785. Resorcinol-type skin lightening agents, which can be synthesized using coumarin as starting material, are disclosed in U.S. Patent Application Publication No. 2004/0042983. However, some of these compounds can be difficult to formulate, or may cause skin irritation.
It would be desirable to have a safe and non-toxic composition for the treatment or prevention of the pigmentation disorders. The compounds and compositions comprising resorcinols described herein fill this need.